The present invention relates to systems and methods for delivering fluids through a flexible biological barrier and, in particular, systems and methods employing microneedles for such purpose.
Intradermal drug delivery is known to he advantageous for a range of different medications and treatments, such as immunization, immunomodulation, gene delivery, dermatology, allergy, hypersensitivity and cosmetics. Conventionally, intradermal drug delivery is performed by a skilled medical professional using a hypodermic needle positioned bevel-up at a shallow angle relative to the skin surface. Care is required to achieve the correct depth of penetration to ensure successful injection within the dermal layers rather than subcutaneously. The bevel-up needle orientation is needed in order to facilitate positive engagement of the needle with the skin surface at such shallow angles and is anyway the standard practice with any acute angle hypodermic needle insertion (including for example for venipuncture into deeper layers). The use of hypodermic needles for intradermal delivery is known to be painful, since nerve endings in the dermal layer are typically severed by the relatively large needles used.
Further, it has been hypothesized that intraepidermal delivery of drugs, such as vaccines, may have a further enhanced biological effect. Despite its promising prospects, this approach has been largely neglected to date since no delivery devices were available for such shallow application.
Much interest has been shown in development of drug delivery devices which do not require skilled operation, for example, for self-administration of drugs by patients. One approach is that of a “mini-needle” device with an actuator which selectively deploys or retracts the needle so as to penetrate to a limited depth within the dermal layers. Examples of such a device are commercially available from Becton, Dickinson & Co. (USA) and are described in U.S. Pat. Nos. 6,843,781, 6,776,776, 6,689,118, 6,569,143, 6,569,123 and 6,494,865. The needle cannula of such devices typically projects between 1 and 2 millimeters, thereby defining the depth of penetration of the delivery system. Since the already-reduced-length bevel of the needle tip itself has a length of at least 0.8 mm, devices based on conventional needle structures of this type (i.e., a hollow metal cylinder with a beveled point) cannot readily be used for sealed fluid delivery to penetration depths less than 1 mm.
As an alternative to conventional needle structures, many attempts have been made to develop “microneedle” structures using various micromachining technologies and various materials. An early example of the “microneedle” approach may be found in U.S. Pat. No. 3,964,482 to Gerstel et al., issued in 1976, which discloses a drug delivery device for percutaneously administering a drug by use of microneedles (projections) of dimensions up to 10 microns to puncture the stratum corneum, thereby allowing the drug to reach the epidermis. The device has multiple needles projecting outwardly from one surface and, in one implementation, delivers a drag from a reservoir via central bores of the microneedles.
In the three decades since Gerstel et al., many microneedle devices have been proposed, but none has yet achieved commercial success as a widespread clinical product due to a number of practical problems. A first major problem of many microneedle designs relates to mechanical weakness of the microneedles which tend to fracture on contact with the skin, particularly when exposed to shear forces due to lateral movement. A second problem relates to blockage of the bores of hollow microneedles due to punching-out of a plug of tissue during insertion through the skin. Additionally, many needle designs have relatively thin walls causing fragility, and a blunt interface, requiring excessive penetration forces to overcome skin elasticity. These problems are effectively addressed by a microneedle structure disclosed in co-assigned U.S. Pat. No. 6,533,949, which is hereby incorporated by reference in its entirety. The aforementioned microneedle structures also help to overcome a further problem of microneedle devices, namely, that of ensuring effective penetration of the highly elastic skin barrier. Various structures and techniques for employing the aforementioned microneedle structure to achieve enhanced penetration are disclosed in co-assigned PCT Patent Application Publication No. WO 03/074102 A2, which is also hereby incorporated by reference in its entirety.
A still further problem which hampers use of microneedles, particularly for intradermal delivery of fluids, is the risk of leakage of fluid around the microneedles. Specifically, injection of fluids through the hollow microneedles typically generates a back-pressure which tends to expel the microneedles from their incisions. Attempts to prevent expulsion of the microneedles by application of downward force (i.e., towards the skin) on the microneedle device compresses the underlying tissue. This compression increases the fluid impedance opposing injection of the fluid, thereby also interfering with delivery of the fluid to the target tissue. Further, in many designs the fluid flow channels extend all the way to the tip, causing a structural dependence between those two elements. This limits the ability to increase flow channel size to allow greater flow without blunting the microneedle and greatly increasing the force required to achieve penetration, and the reaction forces exerted on the structures by the skin.
There is therefore a need for a system and method for delivering a fluid into a flexible biological barrier which would provide a reliable seal between the microneedles and the biological barrier, and which would reduce the aforementioned back-pressure expulsion effect on the microneedles and prevent leakage,